Head and neck cancer (HNC) is the eighth most common cancer worldwide, with an estimated annual global incidence of approximately 650,000 cases and ˜90,000 deaths attributed to this disease per year [1]. HNC comprises a diverse group of tumor types arising from the upper aerodigestive tract, including the lip, nasal and oral cavities, sinuses, pharynx, larynx, and other sites in this anatomical region [2]. The vast majority of HNC diagnoses (>90%) are of squamous epithelial cell origin (oral cavity, pharynx, larynx), and are thus termed head and neck squamous cell carcinomas (HNSCC) [2]. Nasopharyngeal carcinoma (NPC) is a less common distinct HNC in that >90% of cases harbor latent Epstein-Barr virus [3]. At the time of diagnosis, ˜30-40% of HNC patients typically have localized disease, >50% have associated regional disease, and ˜10% harbor distant metastases. In addition to the anatomic and molecular heterogeneity of HNC, most patients present with locally advanced disease, and/or suffer from other co-morbidities, rendering HNC particularly challenging to treat. Despite the advances in therapeutic options over the recent few decades, treatment toxicities and overall clinical outcomes have remained disappointing [4]. For all sites and stages in the head and neck region, 5-year survival rates average ˜50% [5].
Radiation therapy (RT) remains the primary curative modality for HNC. Even the most effective RT regimens achieve local control rates of 45-55%, with disease-free survival rates of only 30-40% for patients with locally advanced head and neck squamous-cell carcinomas (HNSCC) [6]. Furthermore, standard RT administering the maximal tolerable dose, limited by the surrounding critical normal tissues, yet is still associated with significant morbidity. Thus, the development of novel strategies to enhance tumor cell killing, while minimizing damage to surrounding normal cells, is critical to improving the therapeutic ratio of RT. The benefits of chemotherapy or molecularly-targeted agents combined with RT for HNC is strongly supported through the results from randomized trials and meta-analyses [7, 8]. However, these results remain modest; meta-analyses have documented concurrent RT with chemotherapy to offer an absolute survival advantage of only 4.5% at 5 years [7]. The 5-year overall survival rate of HNSCC patients treated with both RT and Cetuximab is still only 45.6% [8], underscoring a continued need for further improvement.
Novel molecular therapies for HNC have been developed and evaluated, ranging from adenovirus-mediated gene therapy [9-11] to anti-sense oligonucleotide (ASO) approaches involving systemically delivered Bcl-2 ASO combined with local tumor RT [12]. More recently, a rapid, cell-based phenotype-driven high-throughput screen (HTS) was developed for the large-scale identification of novel HNC cytotoxics, preferably with radiosensitizing activities [13, 14].
Ionizing radiation (IR) induces a myriad of physico-chemical changes at the cellular and molecular level [15], most of which have not yet been clearly elucidated, suggesting the existence of many unidentified radiosensitizing targets.